title: Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.
abstract: The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes.
authors.affiliation: UPMC Univ Paris 06, UMR_S 975 - UMR 7725, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France; Inserm U 975, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France; CNRS, UMR 7225, Centre de Recherche en Neurosciences, ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France; ICM, Therapeutique Experimentale de la Neurodegenerescence, Paris, France; Department of Neurology, Philipps-University Marburg, Marburg, Germany; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany; Department of Psychiatry, University of Lübeck, Lübeck, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Fischer
authors.forename: Carmen
authors.initials: C
authors.lastname: Noelker
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.forename: Franca
authors.initials: F
authors.lastname: Vulinović
authors.forename: Serge
authors.initials: S
authors.lastname: Guerreiro
authors.forename: Julia
authors.initials: J
authors.lastname: Fuchs
authors.forename: Lixia
authors.initials: L
authors.lastname: Lu
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
authors.forename: Andreas
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D004734:Energy Metabolism; D051379:Mice; D009498:Neurotoxins / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D011339:Probenecid / Q000633:toxicity*; D012402:Rotenone / Q000633:toxicity; D014528:Uricosuric Agents / Q000633:toxicity*
chemical_list: D015259:Dopamine Agents; D009498:Neurotoxins; D014528:Uricosuric Agents; D012402:Rotenone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D042967:Electron Transport Complex I; D011339:Probenecid; D015655:1-Methyl-4-phenylpyridinium
keywords: ATP; MPP
  +; MPTP; Parkinson's disease; mitochondria; probenecid